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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 514-517, (2002)
© 2002 American Thoracic Society

Original Article

Prevention of Gram-Negative Translocation Reduces the Severity of Hepatopulmonary Syndrome

Anne Rabiller, Hilario Nunes, Didier Lebrec, Khalid A. Tazi, Myriam Wartski, Elisabeth Dulmet, Jean-Marie Libert, Christine Mougeot, Richard Moreau, Michel Mazmanian, Marc Humbert and Philippe Hervé

Laboratoire de Chirurgie Expérimentale-UPRES, Centre Chirurgical Marie Lannelongue, Université Paris Sud, Paris; and Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM U-481, Hôpital Beaujon, Clichy, France

Correspondence and requests for reprints should be addressed to P. Hervé, M.D., Centre Chirurgical Marie Lannelongue, 133 avenue de la Résistance, 92350 Le Plessis Robinson, France. E-mail: pherve{at}ccml.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatopulmonary syndrome (HPS) is characterized by intrapulmonary vascular dilatations and an increased alveoloarterial oxygen difference (AaPO2). These abnormalities are related to augmented pulmonary nitric oxide (NO) production, dependent primarily on increases in the expression and activity of inducible NO-synthase (iNOS) within pulmonary intravascular macrophages and, to a lesser extent, of endothelial NOS (eNOS). Production of iNOS by pulmonary intravascular macrophages might be related to translocated gut bacteria present in the pulmonary circulation. To test this hypothesis, we determined whether macrophage sequestration, lung iNOS expression and activity, and HPS severity were decreased after norfloxacin was given for 5 weeks to prevent Gram-negative bacterial translocation in rats with common bile duct ligation–induced cirrhosis. Norfloxacin decreased the incidence of Gram-negative translocation from 70 to 0% and the percentage of pulmonary microvessels containing more than 10 macrophages from 52 ± 7 to 21 ± 8% (p < 0.01). AaPO2 and cerebral uptake of intravenous 99mTc-labeled albumin macroaggregates (reflecting intrapulmonary vascular dilatations) were intermediate to those of untreated cirrhotic and sham-operated rats. The activity and expression of lung iNOS, but not eNOS, were reduced to normal. Norfloxacin may reduce HPS severity by inhibiting Gram-negative bacterial translocation, thereby decreasing NO production by pulmonary intravascular macrophages. Bacterial translocation may be the key to the pathogenesis of HPS.

Key Words: experimental cirrhosis • hepatopulmonary syndrome • macrophage • bacterial translocation • nitric oxide synthase


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In cirrhosis, intestinal bacterial overgrowth, impaired host defenses, and disruption of the gut mucosal barrier may promote bacterial translocation, i.e., dissemination of gut lumen bacteria within the body (1–3). Bacterial translocation has been found in 45–75% of animals with experimental cirrhosis (1–3). Normally, the lung vascular bed is not exposed to large amounts of bacterial products: these are filtered out by the liver, whose Kupffer cells clear nearly all gut bacteria and bacterial endotoxins from the bloodstream (4). In cirrhosis, the development of portosystemic shunts and the dramatic decrease in the phagocytic capacity of the liver allow circulating bacteria or bacterial endotoxins to enter the pulmonary circulation. In this situation, the lungs clear the blood of gut bacteria and endotoxins (3, 4), thereby compensating for the decrease in liver phagocytic function (4). This increase in pulmonary phagocytic activity is ascribable to extensive accumulation of pulmonary intravascular macrophages that adhere to the pulmonary endothelium (4–6). Pathogens that are translocated from the gut to the pulmonary circulation probably cause macrophage sequestration by inducing coordinated expression of macrophage and endothelium adhesion molecules, as well as local release of monocyte chemotactic factors (7, 8). During phagocytosis, activated macrophages release numerous secretory products into the extracellular environment, including cytokines and nitric oxide (NO) (7, 8). Our finding in a recent study (6) that inducible NO-synthase (iNOS) was expressed in the pulmonary intravascular macrophages of cirrhotic rats may explain the increase in lung production of NO in this animal model (6). Rats with cirrhosis induced by common bile duct ligation (CBDL) (6, 9, 10) develop hepatopulmonary syndrome (HPS) with intrapulmonary vascular dilatations, an increased alveoloarterial oxygen difference (AaPO2), and a hyperdynamic state replicating the abnormalities seen in human HPS (11). This syndrome has been shown to result in large part from overproduction of NO in the lung: giving N(G)-nitro-L-arginine methyl ester to normalize lung NO production prevented HPS in cirrhotic rats (6). Taken together, these findings suggest that translocation of gut bacteria in cirrhotic rats may be an important step in the pathogenesis of HPS.

Norfloxacin, a quinolone predominantly active against Gram-negative bacteria, has been shown to prevent bacterial translocation in cirrhotic patients (12, 13). The aim of the present study was to determine whether giving prophylactic norfloxacin treatment to rats with CBDL would decrease pulmonary intravascular macrophages and lung iNOS expression and activity, thereby preventing HPS.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals
The study protocol was reviewed and approved by the institutional animal care committee. Male Wistar rats were subjected to CBDL as previously described (14). Four groups of 20 rats were studied 5 weeks after CBDL or a sham operation: a norfloxacin-treated CBDL group, an untreated CBDL group, a norfloxacin-treated sham-operated group, and an untreated sham-operated group. Norfloxacin was given by gavage after surgery for 5 weeks in a dose of 10 mg kg-1 day-1.

Hemodynamic and Blood Gas Measurements
After anesthesia using intraperitoneal ketamine (100 mg kg-1) and xylazine (0.75 mg kg-1), the rats were ventilated with room air through a tracheotomy. Catheters were inserted into the pulmonary and the tail arteries. A thermistor was positioned in the aortic arch to measure cardiac output. AaPO2 was calculated using the modified alveolar gas equation. Hemodynamic and blood gas values were recorded 30 minutes after the ventilation was adjusted to obtain an arterial carbon dioxide pressure between 35 and 45 mm Hg. At the end of the hemodynamic study, a laparotomy was performed to measure portal pressure, to sample blood from the inferior vena cava for asparate aminotransferase (ASAT) and aspartate alanine transferase (ALAT) measurements, and to remove and weigh the spleen and liver.

Detection of Intrapulmonary Vascular Dilatations
Thirty minutes after the injection of 200 µCi of 99mTc-labeled albumin macroaggregates into the jugular vein, the ratio of brain-over-lung radioactivity was determined (6).

Bacteriology Studies
The rats were anesthetized, and the abdominal skin was shaved and sterilized with an iodine solution. A swab of ascitic fluid from the peritoneal cavity was plated onto chocolate agar plates. Three milliliters of blood was withdrawn from the inferior vena cava and inoculated into aerobic and anaerobic Bactec culture bottles. The mesenteric lymph nodes were dissected and plated onto chocolate agar plates. Any positive mesenteric lymph node cultures were considered indicative of bacterial translocation from the intestinal lumen.

Lung NOS Activity Measurements
Total and calcium-independent NOS activities were measured in lung homogenates by determining the conversion of [14C]L-arginine to [14C]L-citrulline as previously reported (15–18).

Lung NOS Protein Expression
Expression of endothelial NOS (eNOS) and iNOS protein in the lungs was determined using specific antisera against eNOS and iNOS (Transduction Laboratories, Lexington, UK) (15–18). Densitometry results are expressed as percentages of the value in untreated control animals (100%).

Microscopic Examination
Distended lungs (four rats in each group) were fixed by infusion of 10% formalin at a pressure of 25 cm H2O into the trachea. Lung sections (4 µm) were stained with hematoxylin and eosin. We (6) and others (4) have recently shown that small pulmonary vessels of cirrhotic rats had adherent large mononuclear macrophage-like cells strongly immunoreactive for the specific rat macrophage monoclonal antibody ED1. To quantify intravascular macrophage sequestration, 60 vessels per animal were examined and the percentage of vessels with more than 10 mononuclear macrophage-type cells was determined in each group. Only vessels that were circular in cross section were included.

Statistical Analysis
Results were evaluated using analysis of variance followed by Fisher's post hoc tests. Because results were similar in the norfloxacin-treated and untreated sham-operated groups, these were combined for subsequent analysis. All values are reported as means ± SEM. The p values of less than 0.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
All rats subjected to CBDL became jaundiced, and most had ascites and a micronodular liver. Gross and histologic findings at autopsy confirmed that all CBDL rats had cirrhosis. ASAT and ALAT blood concentrations, liver and spleen weights, and portal venous pressure levels were similar in the norfloxacin-treated and untreated CBDL groups. All these values were significantly higher than in the sham-operated animals. Postoperative mortality was less than 1%. Five-week mortality rates were similar in the two groups of CBDL rats (25% with and 27% without norfloxacin).

All lungs from norfloxacin-treated and untreated CBDL rats showed accumulation of large mononuclear macrophage-like cells within the lumen of numerous small muscular and nonmuscular pulmonary vessels. The percentages of vessels with more than 10 adherent macrophages was 52 ± 7% in the untreated CBDL group but only 21 ± 8% in the norfloxacin-treated CBDL group (p < 0.04).

Bacteriology
Culture-positive mesenteric lymph nodes, indicating that translocation had occurred, were found in 67% of norfloxacin-treated CBDL rats and 70% of untreated CBDL rats. Bacterial peritonitis occurred in 25% of untreated CBDL rats and 50% of norfloxacin-treated CBDL rats. Blood cultures were positive in 40% of norfloxacin-treated and untreated CBDL rats. Thus, the overall incidences of positive cultures were similar in the norfloxacin-treated and untreated CBDL animals. However, the organisms recovered from the cultures were very different between these two groups. Gram-positive bacteria were found in 100% of culture-positive specimens of mesenteric lymph nodes, ascites, and blood from the norfloxacin-treated animals, compared with 60% (p = 0.07), 50% (p = 0.04), and 0% (p < 0.0001), respectively, in the untreated CBDL rats. Isolated bacteria in untreated CBDL rats' mesenteric lymph nodes included Enteroccus faecalis, Escherichia coli, Bacillaceae, and Klebsiella pneumoniae. Isolated bacteria in norfloxacin-treated CBDL rats mesenteric lymph nodes included E. faecalis, Streptococcus, Staphylococcus, and Corynebacterium species. No bacterial growth occurred in any of the specimens of mesenteric lymph nodes, ascites, or blood from the sham-operated animals.

Pulmonary Hemodynamics
Untreated CBDL rats exhibited a characteristic hemodynamic pattern of pulmonary and systemic arterial vasodilation with hyperdynamic circulation, as indicated by lower pulmonary and systemic vascular resistance values and higher cardiac index values as compared with the other groups (Table 1). Norfloxacin-treated CBDL rats had total pulmonary vascular resistance values and cardiac index values intermediate to those in the untreated CBDL animals and in the sham-operated animals (Table 1).


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  		TABLE 1. Hemodynamics, brain-to-lung radioactivity ratios, and alveoloarterial o2 differences*

 
Hepatopulmonary Syndrome in Cirrhotic Rats
Assessment of HPS in the CBDL rats was based on the combination of gas exchange abnormalities and intrapulmonary vascular dilatations. Arterial carbon dioxide pressure was similar in all groups. In the untreated CBDL rats, AaPO2 and the ratio of brain-over-lung radioactivity were substantially higher than in the sham-operated animals, reflecting the presence of intrapulmonary vascular dilatations (Table 1). In norfloxacin-treated CBDL rats, AaPO2 and brain-over-lung radioactivity ratio were intermediate to those in the untreated CBDL rats and in the sham-operated rats, indicating less severe HPS than in the untreated CBDL rats (Table 1).

Lung NOS Activities
Total and calcium-independent NOS activities in the lungs were 2.8- and 3.9-fold higher, respectively, in untreated CBDL rats as compared with sham-operated rats (Figure 1) . As compared with untreated CBDL rats, total lung NOS activity was 18% lower and calcium-independent NOS activity 41% lower (p < 0.01) in the norfloxacin-treated CBDL rats. Levels of calcium-independent NOS activities were similar in norfloxacin-treated CBDL and sham-operated animals. Total and calcium-independent lung NOS activities were correlated with each other in the two CBDL groups, indicating that variations in calcium-independent NOS activity accounted for most of the change in total NOS activities (r = 0.89, p = 0.01).



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  		Figure 1. Total and calcium-independent NOS activities in lung homogenates from sham-operated rats, untreated cirrhotic rats, and cirrhotic rats treated with norfloxacin. Results are given as means ± SEM. *Significantly different from sham rats (p < 0.05). {dagger}Significantly different from untreated cirrhotic rats (p < 0.05).

 
Lung NOS Expression
Levels of eNOS protein expression in the lungs increased similarly in norfloxacin-treated and untreated CBDL rats as compared with sham-operated animals (142 ± 10 and 122 ± 7% of sham values, respectively; p < 0.01) (Figures 2 and 3) . As compared with sham-operated animals, iNOS protein expression was higher in the lungs of untreated CBDL rats (260 ± 10% of sham-operated values, p < 0.01). In contrast, no significant difference was found in norfloxacin-treated CBDL rats (37 ± 20% of sham-operated values).



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  		Figure 2. Protein expression of eNOS in lung homogenates from untreated cirrhotic rats, norfloxacin-treated cirrhotic rats, and sham-operated rats. Representative Western blot of eNOS protein in one rat of each group, and bar depicting eNOS protein content quantified by laser densitometry in all three groups. Results are given as means ± SEM of the percentage increase from sham eNOS values. *Significantly different from sham rats (p < 0.05).

 


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  		Figure 3. Protein expression of iNOS in lung homogenates from untreated cirrhotic rats, norfloxacin-treated cirrhotic rats, and sham-operated rats. Representative Western blot of eNOS protein in one rat of each group, and bar depicting iNOS protein content quantified by laser densitometry in all three groups. Results are given as means ± SEM of the percentage increase from sham iNOS values. *Significantly different from sham rats (p < 0.05).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The goal of the present experimental study on the role of bacterial translocation in the pathogenesis of HPS was to determine whether prophylactic norfloxacin treatment prevents HPS in rats with cirrhosis. Norfloxacin decreased the incidence of Gram-negative, but not Gram-positive, bacterial translocation, the number of macrophages sequestered in pulmonary microvessels, the expression and activity of lung iNOS, and the severity of HPS.

As previously reported in human and experimental cirrhosis (1, 2, 12, 13), the incidence of bacterial translocation, i.e., extraintestinal dissemination of gut bacteria, was high in our rats with CBDL-induced cirrhosis: about 70% had positive mesenteric lymph node cultures. Norfloxacin did not reduce the incidence of bacterial translocation to mesenteric lymph nodes, and it did not decrease the incidence of peritoneal infection or bacteremia. However, norfloxacin selected Gram-positive pathogens: all bacteria recovered from blood specimens were Gram-positive in the norfloxacin-treated group and Gram-negative in the untreated group. Similar selection of Gram-positive flora has been reported with norfloxacin prophylaxis in humans and rats with cirrhosis (2, 13).

Although we did not investigate whether the pulmonary intravascular macrophages of our cirrhotic rats contained bacteria, a recent study indicates that the lung becomes the main site of clearance of bacteria and endotoxins in cirrhotic rats (4), thus compensating for the decrease in liver Kupffer cell activity (4). Accumulation of macrophages in the pulmonary microcirculation accounts for this shift in phagocytosis from the liver to the lung. Miot-Noirault and coworkers (4) and Chang and colleagues (5) have demonstrated that these pulmonary intravacular macrophages derive from circulating monocytes, not from emigrating Kupffer cells. In the present study, norfloxacin decreased the number of intravascular macrophages adherent to the pulmonary microvessel endothelium. This cannot be ascribed to a lower incidence of bacteremia, as bacteremia occurred in similar proportions of animals in the two groups. The most likely explanation is a decrease in adhesion molecule expression (19) and/or in proinflammatory cytokine release (20) upon stimulation of macrophages and endothelial cells by Gram-positive bacteria, as compared with Gram-negative bacteria.

In an earlier study of cirrhotic rats, we found an increase in pulmonary NO production related to increased expression and activity of pulmonary intravascular macrophage iNOS and, to a lesser extent, of lung eNOS (6). Norfloxacin markedly reduced iNOS expression and activity in the lungs of these cirrhotic animals. This was probably ascribable to both a decrease in the number of pulmonary intravascular macrophages and a lower level of induction of macrophagic NOS by Gram-positive bacteria (21).

Norfloxacin treatment decreased the severity of HPS in the CBDL rats, as indicated by the intermediate AaPO2 and brain-over-lung radioactivity values between those in sham-operated and in untreated CBDL rats. Pulmonary vascular resistance values were also halfway between those in the sham-operated and untreated CBDL rats. We suggest that the decrease in NO release by the pulmonary intravascular macrophages may account for these results. Support for this hypothesis comes from our previous findings (6) that the magnitude of intrapulmonary shunting (as an index of intrapulmonary vascular dilatation) correlated with the level of pulmonary NO production and that inhibition with N(G)-nitro-L-arginine methyl ester of pulmonary iNOS- and eNOS-derived NO production prevented HPS and pulmonary vasodilatation (6). Prevention of HPS and pulmonary vasodilation was incomplete with norfloxacin. This may be ascribable to the persistent increase in lung eNOS-derived NO production in the norfloxacin-treated CBDL rats. Several studies (1, 22) have demonstrated that eNOS upregulation was a consequence of the increased shear stress caused by hyperdynamic circulation. Thus, the increases in lung eNOS expression and activity might be related to the persistent increase in cardiac index in the norfloxacin-treated CBDL animals.

Factors other than iNOS inhibition may be involved also. One hypothesis is that norfloxacin administration may influence the development of portal hypertension and the natural history of obstructive hepatic injury, thus altering the production and/or metabolism of other mediators by the liver. This hypothesis is ruled out, however, by the similar severity of hepatic injury and portal hypertension in the two CBDL groups.

Our study has important implications. It supports the usefulness of selective intestinal decontamination with norfloxacin previously suggested by prospective studies in which norfloxacin therapy reduced the risk of extra-peritoneal infections in patients with cirrhosis (12, 13). Another potential beneficial effect may be prevention and/or treatment of HPS: recent anecdotal case-report showing resolution of hypoxemia in a patient with HPS treated with norfloxacin supports this possibility (23). Further studies are needed to investigate whether HPS may regress with norfloxacin treatment in rats with established cirrhosis. Lastly, studies (4, 24, 25) indicating that pulmonary phagocytosis occur in patients with cirrhosis also suggest that induction of pulmonary intravascular macrophages might contribute to development of pulmonary vascular disease seen in these patients such as HPS and porto-pulmonary hypertension.

In conclusion, prophylactic treatment of cirrhotic rats with norfloxacin decreased the incidence of Gram-negative but not-Gram-positive bacterial translocation, the number of macrophages sequestered in pulmonary microvessels, the expression and activity of lung iNOS, and the severity of HPS. This study indicates that bacterial translocation may be an important step in the pathophysiology of HPS.


   Acknowledgments
 
:

The authors thank Odile Poirel for her excellent technical assistance.

Received in original form January 15, 2002; accepted in final form May 3, 2002


   REFERENCES
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 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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